Acute joint injury often results in the development of osteoarthritis. Because osteoarthritis affects 1 in 3 individuals in the United States, there is an urgent need to delineate the biomarker response after acute joint injury so the incipient stages of osteoarthritis can be defined. Considerable biomarker research has been performed on patients with advanced disease when medical therapy is unrewarding. However, it is not feasible to periodically sample human patients during the early, subclinical stages of osteoarthritis, thus hindering thorough assessment of biomarkers to identify the onset of osteoarthritis. Our long-term goal is to use biomarkers as a means to establish early diagnosis of osteoarthritis and identify therapies that will slow its progression. The objective of this R15 application is to validate/refute that synovial fluid, serum, and urine biomarkers can be used to identify changes that occur after acute joint injury by using an equine joint injury model. The central hypothesis is that biomarker changes resulting from an acute osteochondral injury in an equine joint will reflect the onset and progression of osteoarthritis. The rationale for this proposal is that once synovial fluid, serum, and urine biomarker response has been defined after acute injury, subsequent definitive studies pertaining to early diagnosis and prevention of osteoarthritis will have been enabled. Identified biomarkers may be used to discover pathways of disease that would allow development of preventative and therapeutic interventions. The resulting knowledge may help to reduce the burdens of human disability. Guided by strong preliminary data, our central hypothesis will be tested by pursuing the following 2 specific aims: 1. Validate/refute that osteochondral injury in the equine metacarpophalangeal joint mimics the clinical and morphological onset and progression of osteoarthritis. Our working hypothesis is that creation of an osteochondral injury will result in clinical, arthroscopic, and histologic changes characteristic of the onset and progression of osteoarthritis. 2. Validate/refute that osteochondral injury in the equine metacarpophalangeal joint will result in biomarker changes reflective of the onset and progression of osteoarthritis. Our working hypothesis is that creation of an osteochondral injury will result in anabolic, catabolic, and inflammatory changes that can be identified using synovial fluid, serum, and/or urine biomarkers and are characteristic of the onset and progression of osteoarthritis. The proposed work is innovative because it uses a translational animal model of osteoarthritis that is both non-terminal and humane, addressing the "reduce, refine, and replace" mandate from NIH. This equine model readily allows serial sampling of synovial fluid, serum, and urine, which enables longitudinal comparison between fluids. Expected outcomes are that the biomarker responses will allow for more accurate measurement of the onset of osteoarthritis for translational application to human disease. PUBLIC HEALTH RELEVANCE: The proposed research has relevance to public health, because the fundamental indicators of the onset and progression of osteoarthritis to be investigated have value to people. Thus, the community that is potentially impacted by this research is the large segment of the population that is at risk to develop osteoarthritis at some point in their lifetime. The potential impact is major because it may reduce the financial impact of osteoarthritis by reducing healthcare costs and enabling individuals to remain at work because of reduced symptoms of the disease.